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Manuela Bartoli, Folami Lamoke, Sean Shaw, Diana Gutsaeva, Babak Baban; Modulation of cytokine trans-signaling by microRNA-21 (miR-21)-mediated regulation of TACE/ADAM17 in the diabetic retina. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1030.
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Up-regulation of inflammatory cytokines and their receptors, soluble and membrane bound, is involved in the pathogenesis of diabetic retinopathy (DR). Here we have investigated the expression levels and activity of the metalloproteinase TACE/ADAM17 which serves as converting enzyme to cleave cytokines receptors and propagate inflammatory responses by cytokines trans-signaling. Furthermore, we have investigated the potential role of microRNA-21 (miR-21) in promoting TACE/ADAM17 disinhibition through suppression of tissue inhibitor of matrix-metalloproteinase 3 (TIMP3) gene expression.
Diabetic retinas were obtained from streptozotocin-induced diabetic rats (STZ-rats) and from human post-mortem samples obtained by Georgia Eye Bank. MiR-21 expression was measured by qPCR and in situ hybridization. QPCR and Western analyses were employed to measure the expression levels of TIMP3 and TACE/ADAM17. A commercially available kit was used to assess TACE/ADAM17 activity.
TACE/ADAM 17 activity was significantly up-regulated in the diabetic retina of STZ-rats (at 4 and 8 weeks of hyperglycemia). Increased TACE/ADAM17 activity was also found in human post-mortem retinas of diabetic donors. QPCR and in situ hybridization demonstrated increased levels of miR-21in the diabetic rat and human retinas. Furthermore, retinal expression levels of TIMP3 were down-regulated in the diabetic retinas at both, mRNA and protein levels.
Our results show that the activity of TACE/ADAM17 is up-regulated in the diabetic retina and this effect correlated with increased miR-21 expression and consequent TIMP3 gene suppression. These data revealed the existence of a key regulatory pathway for cytokine trans-signaling and propagation of inflammatory processes in the diabetic retina.
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